Human cytomegalovirus (HCMV) is a widespread pathogen that is the leading viral cause of birth defects and a major cause of morbidity and mortality in adults who are immunocompromised. It is a life-threatening, opportunistic infection in AIDS and a common post-transplant complication in allograft recipients. HCMV has profound effects on its host cell, deregulating cell cycle progression and modulating the expression of a large number of cellular genes. HCMV also inhibits the recognition of the infected cell by the infected host. The long-term goal of this research program is to elucidate at the molecular level the function of HCMV genes that regulate the interaction of the virus with its host and thereby control the processes of viral replication and pathogenesis. This proposal is focused on the function of four HCMV immediate proteins (pIRS1, pIRS1.5, pTRS1 and IE2) and five HCMV-coded RNAs (UL21.5,UL106-109, TRS2-4, 7, 13) that are packaged in virus particles. Each of these virus products is available during the initial stage of the viral replication cycle and has the potential to regulate the virus-host interaction. Mutant viruses will be constructed lacking the coding regions for these genes, their phenotypes will be characterized, the biochemical basis for the activities of these proteins will be explored, and the mechanism by which RNAs are directed to be packaged in the virion will be investigated.